Drug targeting to endothelial cells (EC) will help to attain more specific and effective treatment of a plethora of maladies including inflammation. We found that targeting prototype nanocarriers and cargoes to the endothelial Cell Adhesion Molecules (CAMs) ICAM-1 and VCAM-1, differentially expressed by resting vs pathologically altered EC, provides prophylactic and therapeutic drug delivery into EC. Further, ICAM-targeted nanoparticles transfer across EC without damage to the cells. Flow conditions, affinity and geometry of anti-CAM carriers govern their biological behavior, EC targeting and sub-cellular destination. Abnormal flow in pathological vascular sites provides both a stimulus for CAM exposure on EC and a mechanism for local binding of wm to EC. To achieve EC targeting with controlled duration and timing of effects, we propose to target to CAMs novel biocompatible stealth PEG-di-block copolimer nanocarriers with controlled geometry designed by our team: worm micelles (wm), spherical polymersomes (ps) and nanoparticles (np), showing prolonged circulation in animals (unprecedentently achieving weeks for wm, due to their alignment with flow). Our hypothesis is that these nanocarriers will serve as highly effective long-circulating carrier platforms for sustained delivery of drugs to, into and across EC using CAM targeting. Spherical carriers are expected to effectively enter and traverse EC, while wm are expected to recognize vascular pathological sites (vascular surveillance). This will be tested in the following Specific Aims in vitro and in vivo: 1. Refine anti-CAM targeted polymer carriers with controlled geometry/affinity and define their endothelial targeting; 2. Define intra-and transcellular transport of these anti-CAM carriers and effects of flow and EC phenotype in control of these processes; 3. Evaluate potential side effects and anti-inflammatory utility of these anti-CAM carriers. These studies will provide: i) proof of principle for EC targeting of stealth polymer nanocarriers; and, ii) insight into the role of flow, carrier geometry and affinity in targeting to EC and EC responses (e.g., endocytosis and activation) to targeting. Bearing in mind the central roles of EC as a gate-keeper of vascular transport and as a target and barrier for delivery of drugs for treatment of cardiovascular, oncological, metabolic and other maladies, this is a globally important goal for the field of drug delivery. Public Health Relevance: Targeted delivery of drugs to endothelial cells lining vasculature will advance treatment of many health maladies. In this grant, we will design and test a novel drug delivery platform based on targeted recognition of endothelial surface determinants by polymer nanocarriers loaded by anti-inflammatory and other therapeutic agents.